In low-oxygen conditions, breast cancer cells form structures that facilitate movement, such as filaments that allow the cell to contract (green) and cellular "hands" that grab surfaces to pull the cell along (red). (Credit: Daniele Gilkes)

Breast cancer spreads when tumors can’t ‘breathe’

Lack of oxygen inside a breast cancer tumor can trigger the chain of events that spreads the disease throughout the body, biologists say.

The discovery explains how tumors produce two proteins that transform breast cancer cells from rigid and stationery to mobile and invasive—and may lead to new strategies for interrupting the spread of tumors, the process called metastasis.

“High levels of RhoA and ROCK1 were known to worsen outcomes for breast cancer patients by endowing cancer cells with the ability to move, but the trigger for their production was a mystery,” says Gregg Semenza, professor of medicine at Johns Hopkins University School of Medicine.

“We now know that the production of these proteins increases dramatically when breast cancer cells are exposed to low-oxygen conditions.”

To move, cancer cells must make many changes to their internal structures, says Semenza. Thin parallel filaments form throughout the cells, allowing them to contract. Cellular “hands” rise up allowing cells to “grab” external surfaces to pull themselves along. The proteins RhoA and ROCK1 are known to be central to the formation of these structures.

The genes that produce RhoA and ROCK1 are known to be turned on at high levels in metastatic breast cancers. In a few cases, those increased levels can be traced back to a genetic error in a protein that controls them, but not in most. This led Semenza to search for another cause for the high levels.

Master control proteins

“As tumor cells multiply, the interior of the tumor begins to run out of oxygen because it isn’t being fed by blood vessels,” Semenza explains. “The lack of oxygen activates the hypoxia-inducible factors, which are master control proteins that switch on many genes that help cells adapt to the scarcity of oxygen.”

While that response is essential for life in normal cells, hypoxia-inducible factors also turn on genes that help cancer cells escape from the oxygen-starved tumor by invading blood vessels, through which they spread to other parts of the body.

Daniele Gilkes, a postdoctoral fellow and lead author of the report, analyzed human metastatic breast cancer cells grown in low oxygen conditions in the laboratory. She found that the cells were much more mobile in the presence of low levels of oxygen than at physiologically normal levels. They had three times as many filaments and many more “hands” per cell.

When the hypoxia-inducible factor protein levels were knocked down, though, the tumor cells hardly moved at all. The numbers of filaments and “hands” in the cells and their ability to contract were also decreased.

Preventing metastases

When Gilkes measured the levels of the RhoA and ROCK1 proteins, she saw a big increase in the levels of both proteins in cells grown in low oxygen.

When the breast cancer cells were modified to knock down the amount of hypoxia-inducible factors, however, the levels of RhoA and ROCK1 decreased, indicating a direct relationship between the two sets of proteins. Further experiments confirmed that hypoxia-inducible factors actually bind to the RhoA and ROCK1 genes to turn them on.

The team then took advantage of a database that allowed them to check whether having RhoA and ROCK1 genes turned on in breast cancer cells affected patient survival. They found that breast cancer patients with high levels of RhoA or ROCK1, and especially those with high levels of both, were much more likely to die of breast cancer than those with low levels.

“We have successfully decreased the mobility of breast cancer cells in the lab by using genetic tricks to knock the hypoxia-inducible factors down,” Gilkes says.

“Now that we understand the mechanism at play, we hope that clinical trials will be performed to test whether drugs that inhibit hypoxia-inducible factors will have the double effect of blocking production of RhoA and ROCK1 and preventing metastases in women with breast cancer.”

The National Cancer Institute, Johns Hopkins Institute for Cell Engineering, the American Cancer Society, and the Susan G. Komen Breast Cancer Foundation supported the research.

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